5^th Asia-Pacific Summit on Cancer Therapy July 20-22, 2015 Brisbane, Australia

Eun Kyung Lee receieved her Ph.D. in Molecular and Cellular Biology from Gwangju Institute of Science and Technology (GIST), South Korea in 2006. She has completed postdoctoral training at Johns Hopkins Medical Institutes and National Institutes of Health/National Institute on Aging (NIH/NIA), USA from 2007 to 2011. She is an assistant professor at Catholic University of Korea, College of Medicine since 2011. Her research interests are focused to RNA metabolism between health and diseases including cancer. Her group studies molecular mechanisms of RNA regulation by RNA binding proteins or non-coding RNAs in mammalian models of tumorigenesis, epithelial-mesenchymal transition, and senescence

p130Cas regulates cell adhesion and migration by mediating tyrosine receptor kinase signaling. Tight regulation of p130Cas expression is critical for the maintenance of cell motility, survival and apoptosis in various cell types. Several studies reveal that transcriptional and post-translational control of p130Cas is important to maintain its expression and activity. To explore novel regulatory mechanisms for p130Cas expression, we investigated the effect of microRNAs on p130Cas level in human breast cancer cells. Here, we provide experimental evidences that miR-329 is a novel factor regulating p130Cas expression. miR-329 down-regulates cell migration and invasion thereby suppress tumor growth via down-regulating p130Cas. Ectopic expression of p130Cas restored the inhibitory effects of miR-329 in tumor progression. Interestingly, relative expression of miR-329 and p130Cas is inversely correlated between normal and breast cancers; miR-329 decreased, while p130Cas increased in breast cancers. Taken together, our results suggest that miR-329 is a novel factor regulating p130Cas expression and aberrant expression of p130Cas is responsible for tumor progression in breast cancers.

Soon-Sun Hong is a professor in the Translational Research Center, Department of Biomedical Sciences, at the Inha University, South Korea.

Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action. Crizotinib strongly suppressed the growth and proliferation of pancreatic cancer cells in a dose-dependent manner. Also, it induced apoptosis by modulating its related factors. In the study, with regard to the mechanism of action, Crizotinib did not inhibit c-MET expression on pancreatic cancer cells; instead, it specifically inhibited the activity of ALK, which was identified to be highly expressed on various pancreatic cancer cells and tissues in our study. In 42 different receptor tyrosine kinase (RTKs) array, Crizotinib also strongly inhibited the expression of activated ALK in pancreatic cancer cells, modulating its downstream mediators such as STAT3, AKT, and ERK. Furthermore, Crizotinib inhibited angiogenesis in a mouse Matrigel plug assay as well as the progression of tumor growth in a mouse xenograft model. Taken together, our investigation shows that Crizotinib inhibits the ALK signaling pathway in pancreatic cancer, resulting in cell growth/angiogenesis inhibition and apoptosis induction. We suggest that Crizotinib might be used as a novel therapeutic drug for treating pancreatic cancer.

Wenyi Gu is a researcher in the School of Biomedical Sciences, University of Queensland, Australia.

Colon cancer is one of the most common cancers in men and women worldwide with high mortality. The major issue in colon cancer treatment is drug-resistance and metastasis. Recent years, cancer stem cells have been recognised to be responsible for drug resistance and metastasis. In this study, we isolated colon cancer stem-like cells through sphere culture and verified with cancer stem cell markers such as CD133, CD44, and CD24. We demonstrated that the inhibition of PI3K/Akt/mTOR pathway by a dual inhibitor BEZ235 suppressed the growth of colon cancer stem cells through reducing their stemness in term of CD133 and Lgr5 expressions. Our data also showed that PI3K/Akt/mTOR pathway was highly activated in colon cancer stem cells, indicating the potential usefulness of targeted therapy against this pathway in eliminating colon cancer stem cells. In cultured colon cancer HCT-116 cells, BEZ235 also markedly decreased the cancer stem cell marker CD133 and Lgr5 levels. Signalling pathway analysis indicated that BEZ235 decreased the activation status of the pathway, evidenced by the decrease of phosphorylated Akt and mTOR after BEZ235 treatment. The role of the pathway in colon cancer stemness was further verified by the treatment of insulin, a known factor activating the PI3K/Akt pathway. We showed that insulin treatment could increase CD133 expression and decreased the effects of BEZ235 on colon cancer stemness and colon cancer cell survival. Our data collectively suggest that PI3K/Akt/mTOR pathway plays an important role in colon cancer stem cells and BEZ235 is a good drug candidate for colon cancer treatment.

Mu-Kuan Chen works in the Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan

Extensive research supports the administration of herbal medicines or natural foods during cancer therapy. Pterostilbene, a naturally occurring phytoalexin has various pharmacological activities including antioxidant activity, cancer prevention activity and cytotoxicity to many cancers. However, the effect of pterostilbene on the autophagy of tumor cells has not been clarified. In this study, the unique effects of pterostilbene on the autophagy of human oral cancer cells were investigated. The results of this study showed that pterostilbene effectively inhibited the growth of human oral cancer cells by inducing cell autophagy. In addition, the formation of acidic vesicular organelles (AVO) and LC3-II production also demonstrated that pterostilbene induced autophagy. Pterostilbene-induced autophagy was triggered by activation of JNK1/2 and inhibition of Akt, ERK1/2, and p38. Administering specific MAPK inhibitors exerted differing effects on the pterostilbene-induced death of human oral cancer cells. This study demonstrated that pterostilbene caused autophagy in human oral cancer cells suggesting that pterostilbene could serve as a new and promising agent for treating human oral cancer.

Khalid Almutairi is working at King Saud University, Saudi Arabia

Colorectal cancer (CRC) is one of the most prevalent cancers in the world. Reports from Saudi Cancer Registry (SCR) showed that colorectal cancer (CRC) was the second most widespread malignancy among Saudis. Colorectal cancer and its treatment can have an adverse effect on social functioning including work and productive life; relationships with friends, relatives and partners; another social activities and interests. Less is known, however, about how colorectal cancer patients in Saudi Arabia (KSA) rate their overall quality of life (QOL) and how they cope with the awareness of living with a chronic and potentially life-threatening disease. We therefore initiated population-based study to describe the QOL of patients with colorectal cancer in Saudi Arabia. This was a descriptive cross-sectional study conducted between September and December 2014 including 106 participating respondents from five public tertiary level hospitals in KSA. Quality of life was assessed using a specific arabic versions of the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30 and QLQ- C29). CRC survivors reported favorable overall global quality of life. They showed good functioning on most QLQ-C30functional scales with the lowest score for emotional functioning. Factors associated with a major reduction in all domains of quality of life included employment status and tumor location. The most bothersome symptoms were fatigability, insomnia and pain. This study identifies the categories of CRC survivors at risk of poorer quality of life and the issues that most need to be addressed in KSA.

Tania Kamal is a PhD student at The University of Auckland, New Zealand.

The discovery of CALR mutations in myeloproliferative neoplasms highlighted importance of Ca2+ homeostasis in megakaryocytic cells. Megakaryocytes express N-methyl-D-aspartate receptors (NMDARs) known to mediate glutamate-induced Ca2+ entry in other cells. However, the roles of glutamate and NMDARs in normal and malignant megakaryocytes are not known. The aim of this study was to determine whether NMDARs provide a novel pathway for Ca2+ entry into leukaemic megakaryoblasts and if so, whether modulating NMDAR activity could influence leukaemia cell growth. Expression of NMDAR subunits was examined in human bone marrow including neoplastic and megakaryoblastic leukaemia cell lines (Meg-01, Set-2 and K-562). Well-established NMDAR modulators (agonists and antagonists) were employed to determine NMDAR effects on the levels of intracellular Ca2+, cell viability, proliferation and differentiation. We found that human leukaemic cells expressed distinct combinations of the NMDAR subunits. Low concentrations of glutamate and NMDAR antagonists (riluzole, memantine, MK-801 and AP5; 5-100 µM) attenuated cell growth in culture mostly through the inhibition of cell proliferation. The use-dependent NMDAR antagonist, memantine (100 µM) reduced Meg-01 viability to 16±10% of controls (IC50 20 µM) and inhibited Meg-01 proliferation to 41±6% (IC50 36 µM). Further, after three days in the presence of NMDAR antagonists, cells acquired morphologic and immunophenotypic features of megakaryocytic differentiation. Our findings indicate that NMDARs provide a novel pathway for Ca2+ entry into leukaemic megakaryoblasts that supports cell proliferation. NMDAR inhibitors counteract these effects suggesting a novel way to interrupt growth of this type of leukaemia.

Su Young Kim is a professor in the Department of Pathology, College of Medicine at The Catholic University of Korea.

During the translation processes of genes, many of the gene products go through a series of modifications to acquire specific functions and biochemical characteristics. UBB, SUMO1, SUMO2, SUMO4, and NEDD8 are representative protein modification genes that control ubiquitination, sumoylation, and neddylation. The alterations of the posttranslational modifications and the associated gene expressions were reported in several disease states, including cancers. We designed this study to find out the expression changes of the protein modification genes and their clinical significance in invasive ductal carcinoma (IDC) of the breast. Using 103 cases of the archival breast cancer tissues diagnosed as IDC, we screened the expression patterns of the protein modification genes by immunohistochemistry. We tested the relationship between the gene expressions and clincopathological parameters. In addition, we analyzed disease free survivals of the cases with respect to the gene expressions. Among the genes we screened, UBB, SUMO1 and SUMO4 did not show any significant association with clinicopathological parameters of IDC. On the contrary, SUMO2 and NEDD8 were associated with T stage. In the analysis is of disease-free survival, double-negative (SUMO2 and NEDD8) cases showed a tendency of worse survival than others.

Wannian Yang was acquired his Ph.D. degree in 1993 at North Carolina State University. He was trained as a postdoctoral fellow in St. Jude Children’s Research Hospital. In 1995, Dr. Yang was appointed as a research associate and later a senior research associate in Dr. Richard Cerione’s laboratory in Department of Molecular Medicine at Cornell University. In 2002, Dr. Yang moved to Weis Center for Research as a Staff Scientist to establish his own laboratory. Dr. Yang has been worked on cellular signaling, particularly tyrosine phosphorylation and ubiquitination signaling, in cancer cells for many years. His major findings include identification of Cdc42-associated kinase 2 (ACK2), discovery of roles of ACK in cell adhesion, receptor-mediated endocytosis and epidermal growth factor receptor (EGFR) signaling. His recent research has found that the ACK regulates EGFR phosphotyrosine signaling in lung cancer cells and the E3 ubiquitin ligase Nedd4-1 promotes gastric cancer metastasis

Background: Gastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric carcinoma. New molecular markers and therapeutic targets are needed for diagnosis, prognosis and treatment of GCA. This study is to establish the E3 ubiquitin ligase Nedd4-1 as a prognostic biomarker to predict the survival and guide the treatment of GCA patients. Methods: Expression of Nedd4-1 in 214 GCA tumor samples was detected by immunohistochemistry staining (IHC) using tissue microarray assay (TMA). Association of Nedd4-1 with cumulative survival of the TNM stages I-III patients and clinicopathological characteristics was statistically analyzed. The role of Nedd4-1 in gastric cancer cell migration and invasion were determined by transwell and wound healing assays. Results: Nedd4-1 is overexpressed in 83% of the GCA tumors. The 5-year survival rate in Nedd4-1 negative GCA patients is as high as 96%. Log-rank analysis indicated that overexpression of Nedd4-1 is inversely correlated with cumulative survival (2 = 21.885, p <0.001). Multivariate logistic regression analysis showed that overexpression of Nedd4-1 is associated with an extremely low GCA survival rate with a hazard ratio (HR) =0.068 (p=0.008) in TNM stages I-III patients. Statistical analysis of association of Nedd4-1 overexpression with clinicopathological characteristics revealed that overexpression of Nedd4-1 is tightly associated with TNM stage (p<0.001). Knockdown of Nedd4-1 in gastric cancer cell lines AGS and N87 dramatically inhibited the gastric cancer cell migration and invasion. Conclusions: Our results indicate that Nedd4-1 is an exceptional prognostic biomarker for GCA and suggest that Nedd4-1 may play an essential role in GCA metastasis

Gin-Shin Chen has completed his Ph.D. at the age of 28 years from National Cheng-Kung University and postdoctoral studies from National Health Research Institutes (NHRI) in Taiwan. He is the associate investigator of the institute of Biomedical Engineering and Nanomedicine of NHRI. His research interests include therapeutic ultrasound, ultrasonic transducers, and medical devices. He has published 17 papers in reputed journals.

Noninvasive treatment of cancers has been implemented using high-intensity focused ultrasound (HIFU). Ultrasound waves are generated by a non-imaging transducer outside the body, propagated via ultrasonic medium and various tissues, and converged on a small region at the focus of the transducer. In short time, HIFU and induced hot spot are formed within the focal region. The hot spot targets the cancer cells under imaging guidance to cause coagulative necrosis. Consequently, HIFU can achieve local and precise ablation of cancers without incision. Breast cancer is the most common cancer in women worldwide. Image-guided HIFU has been applied to treat breast cancer. However, two clinical issues were encountered due to the design of HIFU transducers. A spherical bowl transducer was designed to emit ultrasound beams into the breast from the anterior to the posterior when the patient lay prone, which resulted in that the HIFU burned the chest bone and muscles behind the beast cancer. The other problem is skin burn in the period of HIFU ablating cancer. The acoustic window of the present HIFU transducer on the skin is so small that the heat per unit area is highly sufficient to burn the skin. Therefore, we have developed a HIFU device dedicated for breast cancer treatment in this investigation. The HIFU device consisted of sixteen identical piezoelectrical resonators and the resonators were placed to form a ring with a diameter of 20 cm. The acoustic path of the ring-shape HIFU transducer was more parallel to the chest wall as compared with current transducers, which may prevent chest bone and muscles from thermal damage. The design of ring shape can also increase the acoustic window on the skin to avoid skin burn when HIFU ablates the cancer near the skin. The ring HIFU prototype was fabricated and characterized. The pork ablation of the self-developed HIFU device was performed to verify the feasibility of our concept.

Yee Syuen LOW is a Research Scientist in the Department of Colorectal Surgery, at the Singapore General Hospital.

Colorectal cancer (CRC) is one of the highest incidence cancers worldwide. In Singapore it is the second and third leading cause of cancer mortality in males and females respectively. Early-stage CRC patients are considered curative after surgery. Nevertheless, up to 25% of these patients still succumb to metastasis and subsequently leads to mortality. Gene expression profiling has been widely studied to identify biomarkers for recurrence or metastasis in early-stage CRC in different populations. Nonetheless, Hong et al (2010) reported that the metastasis signatures identified in Caucasian populations were not reproducible in Singapore Chinese population. The aim of this project is to determine whether a combination of expression and mutation signatures is able to predict metastasis accurately for better prognosis and informed use of adjuvant therapy in early-stage sporadic Chinese CRC patients. We have previously reported a metastasis signature arrayed from 70 fresh frozen samples, with an estimated accuracy of 71% (Hong et al, 2010). In this project, additional 80 fresh frozen samples were selected with identical inclusion criteria and arrayed on the same platform. We identified a 193 genes-metastasis signature from the combined 150 samples with 70% metastasis prediction accuracy. The 193 gene-set was translated onto Nanostring nCounter platform and arrayed on the same 150 FFPE samples. Preliminary results show that the 193 gene-set has similar predictive accuracy on FFPE samples, a more commonly used method of archiving samples worldwide. The gene-set will be further validated on an independent set of 150 FFPE samples. In addition, mutation profiles of 20 commonly known genes in CRC were investigated on the same 150 samples by amplicon targeted sequencing. Preliminary results indicate that the mutation profiles of several genes were significantly different between metastasis-positive and -negative samples and the combination of mutation and expression signatures might increase the metastasis prediction accuracy.

Flávio Monteiro Ayres has completed his M.Sc. in 2000 from the Federal University of Goiás (Brazil), his Ph.D. in 2005 from Niigata University (Japan) and postdoctoral studies from Universidade Estadual de Campinas (UNICAMP). He is the coordinator of the Laboratory of Genetics Research in the Estadual University of Goiás (UEG). He has published 16 articles, most of them on cancer genetics. F.M. Ayres has been granted with a research fellowship from UEG (Programa de Incentivo à Pesquisa e Produção Científica – PROBIP) and International Travel support from Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG – CH-01/2015).

Colorectal cancer (CCR) is the third more incident cancer worldwide and the second more frequent in developing countries. In Brazil, mortality due to CCR has markedly increased in the last few decades, being the fifth cause of mortality in both genders. To investigate the implications of the TP53 R72P polymorphism in CCR risk, genotyping was performed by ASO-PCR. Subjects clinical data were collected from the hospital files. A database for meta-analysis was built according to the continents and considering genotype frequencies, sample size from 17 selected relevant studies. Among 80 CCR patients, 52% were male, 34% smokers and 28% alcoholic. Genotype frequencies were 76, 21 and 3% for Arg/Arg, Arg/Pro and Pro/Pro, respectively. Patients mean age was 60 y.o. (25-87 y.o.). Pro/Pro genotype was associated with later CCR development and the Arg/Arg was the most frequent genotype in all the four tumor TNM stages, ranging from 67 to 87%. No association was found between R72P genotypes and CCR risk, age development, five years survival rates or family history of cancer. Patients data were compared with a control group data composed by 85 health subjects. A significant association between the R72P and CCR increased risk in South America was found when a large sample size (4,338 cases and 6,261 controls) was investigated by meta-analysis.